Structure-activity relationships between antibacterial activities and physicochemical properties of sulfonamides

Relationships between the antimicrobial activities of sulfonamides and physicochemical properties including the acid dissociation constant (pK(a)) and the hydrophobicity constant (pi) were determined. The minimal inhibitory concentrations (MIC) of sulfonamides against Actinobacillus pleuropneumoniae, a gram-negative veterinary pathogen, were used. High performance liquid chromatography was applied for the determination of the electronic and hydrophobic parameters. Empirically determined relationships pointed out the dominant role of the degree of ionization on the antimicrobial activity. The data indicate that hydrophobic properties of sulfonamides, characterized by pi, are of minor importance for the in vitro antibacterial activity. Because of the restricted pK(a) range (4.9-7.7) it could not be established whether the relationship between pK(a) and activity was linear or bilinear. Whenever o,m-disubstituted sulfonamides were included correlations decreased substantially. Relationships based on multicompartment equilibrium models were derived and indicated a bilinear relation between pK(a) and MIC. Model-based equations showed that the antibacterial activity was governed by the extracellular ionic concentration of the sulfonamides whenever different intra and extracellular pH values were assumed in the equilibrium model. The antimicrobial activities of the sulfonamides against gram-positive organisms were also related to the degree of ionization of the sulfonamides in the agar medium.